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Toxicity-Reducing Potential of Extracorporeal Affinity Adsorption Treatment in Combination With the Auristatin-Conjugated Monoclonal Antibody BR96 in a Syngeneic Rat Tumor Model

Nilsson, Rune LU ; Mårtensson, Linda LU ; Eriksson, Sophie LU ; Sjögren, Hans Olov LU and Tennvall, Jan LU (2010) In Cancer 116(Suppl. 4). p.1033-1042
Abstract
BACKGROUND: Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 1001000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment. METHODS: Rats were... (More)
BACKGROUND: Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 1001000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment. METHODS: Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated. RESULTS: Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity. CONCLUSIONS: Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies. (C) 2010 American Cancer Society. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
auristatin, rat, extracorporeal, immunoconjugate, toxicity, colon carcinoma
in
Cancer
volume
116
issue
Suppl. 4
pages
1033 - 1042
publisher
John Wiley & Sons
external identifiers
  • wos:000274316000005
  • scopus:76249100838
ISSN
1097-0142
DOI
10.1002/cncr.24790
language
English
LU publication?
yes
id
4e4becf1-cd7e-43b1-952d-90a5d7fd22e9 (old id 1571122)
date added to LUP
2010-03-16 15:12:37
date last changed
2018-05-29 10:49:36
@article{4e4becf1-cd7e-43b1-952d-90a5d7fd22e9,
  abstract     = {BACKGROUND: Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 1001000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment. METHODS: Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated. RESULTS: Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity. CONCLUSIONS: Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies. (C) 2010 American Cancer Society.},
  author       = {Nilsson, Rune and Mårtensson, Linda and Eriksson, Sophie and Sjögren, Hans Olov and Tennvall, Jan},
  issn         = {1097-0142},
  keyword      = {auristatin,rat,extracorporeal,immunoconjugate,toxicity,colon carcinoma},
  language     = {eng},
  number       = {Suppl. 4},
  pages        = {1033--1042},
  publisher    = {John Wiley & Sons},
  series       = {Cancer},
  title        = {Toxicity-Reducing Potential of Extracorporeal Affinity Adsorption Treatment in Combination With the Auristatin-Conjugated Monoclonal Antibody BR96 in a Syngeneic Rat Tumor Model},
  url          = {http://dx.doi.org/10.1002/cncr.24790},
  volume       = {116},
  year         = {2010},
}